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Heterogeneity in Circulating Tumor Cells: the Relevance of the Stem-Cell Subset

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Heterogeneity in Circulating Tumor Cells: the Relevance of the Stem-Cell Subset cancers Review Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset Chiara Agnoletto 1 , Fabio Corrà 1, Linda Minotti 1 , Federica Baldassari 1, Francesca Crudele 1 , William Joseph James Cook 2 , Gianpiero Di Leva 2, Adamo Pio d’Adamo 3,4 , Paolo Gasparini 3,4 and Stefano Volinia 1,* 1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] (C.A.); [email protected] (F.C.); [email protected] (L.M.); [email protected] (F.B.); [email protected] (F.C.) 2 School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK; [email protected] (W.J.J.C.); [email protected] (G.D.L.) 3 Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy; [email protected] (A.P.d.); [email protected] (P.G.) 4 Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy * Correspondence: [email protected]; Tel.: +39-0532-455714 Received: 1 February 2019; Accepted: 30 March 2019; Published: 5 April 2019 Abstract: The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity. Keywords: CTC; EMT; stemness; CSC 1. Introduction Despite recent medical advances, metastasis, tumor relapse, a lack of effective therapies, and drug resistance remain the major causes of death for tumor patients [1–5]. Research on circulating tumor cells (CTCs), which have been detected in the majority of epithelial cancers [6,7], is a dynamic field of translational and basic research, with more than 270 clinical trials having evaluated CTC enumeration as a biomarker [8]. Further, several studies on CTCs aimed to understand critical pathways that mediate cancer dissemination, and may not be apparent in primary or metastatic tumors. Cancer metastasis occurs when tumor cells dissociate from a primary tumor and migrate to distant organs through the peripheral vasculature [1,9–12]. Cancer cells within the primary tumor lose cell-cell adhesion and acquire features of invasiveness and motility due to epithelial-to-mesenchymal Cancers 2019, 11, 483; doi:10.3390/cancers11040483 www.mdpi.com/journal/cancers Cancers 2019, 11, 483 2 of 36 transition (EMT), leading to their intravasation and survival in blood or lymph vessels, and finally their extravasation at distant sites; here they are subjected to mesenchymal-to-epithelial transition (MET), and proliferate to establish metastatic lesions [12–14]. Whether the release of CTCs into the circulation is a predetermined biological process still remains a debatable matter. Cancer cells can enter circulation long before a tumor is diagnosed; the majority of cells die and only a minor fraction contains viable metastatic precursors that infiltrate organs and survive as disseminated seeds for eventual relapse [1,15]. Therefore, metastatic colonization might be a highly inefficient process, but once it is established, current treatments generally fail to provide persistent responses [12]. Tumors are thought to arise from mutant normal stem cells in their native niches, or from the progeny of cells that retain their tumor-initiating capacity [16,17]. Once at distant sites, these cells survive and proliferate through interactions with specialized niches [18]. Data from a number of studies demonstrate that CTCs with stemness properties exist and represent the most aggressive tumor cells in circulation [19,20]. In this review, we will discuss current concepts and will address questions relative to the heterogeneity of CTCs and the presence of cancer stem cells circulating in the bloodstream (See Table1). 2. Heterogeneity of CTCs CTCs are very rare cancer cells released from a primary tumor. A lot of evidence documents that CTCs represent a heterogeneous pool of tumor cells [8], with highly variable, but generally short, survival times; nevertheless, the pool of these cells in the bloodstream can be continuously replenished by the release of replicating tumor cells in metastatic foci, and thus relates to cancer dormancy [21,22]. To date, relatively little is known regarding the number of CTCs in cancers, their molecular and biological heterogeneity, and their functionalities [9]. Although heterogeneity in CTCs has not yet been fully defined, a fraction of these cells are thought to be viable metastatic precursors capable of initiating a clonal metastatic lesion [9]. A subset of CTCs is represented by inactive non-cycling cells, termed dormant cancer cells [23], which act as latent tumor-initiating seeds and eventually reawaken, and might not respond to chemotherapeutics used in clinics [8,12]. By uncovering phenotypes of CTCs, CTC heterogeneity would be dissected in relation to metastatic competence [19,24]. Recently, clusters of CTCs, consisting of 2–50 cells, have been detected in the vasculature of patients with cancers of different origins, which arise from oligoclonal tumor cell groupings, including breast, prostate, pancreatic, glioblastoma, head and neck cancers [24–33]. Cells within micro-clusters might be protected either from anoikis, associated with the loss of cell-cell adhesion and attachment to the basement membrane, or shear stresses in the circulation [25–27]. Both the structural deformability of aggregated cells and the presence of vascular shunts may allow CTC-clusters to circulate, while inducing a rapid clearance within distal tissues [25]. Although rare, CTC-clusters present a dramatically enhanced metastatic potential, as confirmed in mouse models, and by the adverse prognosis in patients with high numbers of CTC-clusters [12,30,34]. Additionally, neutrophils directly interact with CTCs, defining CTC–neutrophil clusters, and support cell cycle progression in circulation. This interaction in turn leads to more efficient metastasis generation and represents key vulnerabilities of the metastatic process for drug targeting in breast cancer [35]. Mesenchymal transcripts were found to be expressed in tumor cells from CTC-clusters in a human breast tumor, conferring both migratory and stem-like properties [32]. A recent study has suggested that the coexpression of EpCAM, CD44, CD47, and MET in CTCs identifies a subset of cells with increased metastatic capacity [36]. Novel mediators of metastasis have been identified by comparing clusters of tumor cells, captured by using a negCTC-iChip, with single CTCs from breast cancer patients: single cell-resolution RNA sequencing demonstrated the significantly divergent expression of only a few genes, including plakoglobin [25]. Plakoglobin functions as an intercellular tether that confers added metastatic potential to tumor cells in the circulation. Knockdown of plakoglobin inhibits CTC-cluster generation and lung metastases, Cancers 2019, 11, 483 3 of 36 while both abundance of CTC-clusters and high plakoglobin levels denote adverse outcome in breast cancer patients [25], pointing to CTC-clusters as critical mediators of cancer metastasis. 2.1. Partial Mesenchymal Transition in CTCs Recent data support the hypothesis that CTC profile changes occur during tumor cell dissemination, in order to enter into the vasculature, survive in circulation, extravasate, and generate secondary tumors [19,37–39]. Thus, in response to signaling proteins released by stromal cells, tumor cells undergo reversible phenotypic change, described as epithelial-to-mesenchymal transition (EMT) [12,39–43]. EMT is also required in tissue repair; consistently, the metastatic process is at least in part similar to tissue regeneration [14,40,44]. EMT results in a reduced expression of epithelial markers, and an increased plasticity and capacity for migration and invasion, as well as a resistance to anoikis and apoptosis, and senescence, which are hallmarks required for CTC survival and dissemination [14,29]. Studies of the effects of EMT in CTCs have suggested that mesenchymal transformation may facilitate the initial steps of the metastatic cascade, but may reduce their competence to initiate overt metastases [19,45,46]. Disseminated cancer cells may at least partially revert to an epithelial phenotype to promote adhesion and proliferation in distal sites, through mesenchymal–epithelial transition [2,44,47,48]. Cancer-associated EMT
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